The research program proposed in this Multi-Project IPCP application is designed to address basic and preclinical issues associated with the development of a multi-epitope DNA vaccine for immunotherapy of HIV- 1 infected patients. The central strategy of the program is to induce cellular immune responses, cytotoxic T lymphocytes (CTL) and helper T- lymphocytes (HTL), specific for conserved epitopes in both structural and regulatory proteins of HIV-1 in infected patients receiving HAART. Thus, the final goal of the program is to test this strategy directly in a HIV-1 infected patients. To accomplish this goal, a team of individuals from academia (the University of Wisconsin Regional Primate Research Center and the University of Colorado Health Science Center) and Industry (Epimmune, Inc.) With different areas of expertise has been assembled. The HIV-1 derived and HLA-restricted CTL and HTL epitopes needed to design and construct the experimental vaccines are now known, as the result of soon-to-be-completed studies The questions to be answered under preclinical part of this IPCP program concern the optimal design of epitope-based DNA vaccines (Project #1), methods of delivering these vaccines using non-viral DNA vaccine delivery technologies (project #2) and the characterization of the responses that HTL epitopes induce in HIV-1 infected and vaccinated individuals (project #3). The clinical part of the program is designed to allow for the evaluation of a single multi-epitope DNA vaccine formulation with the immunogenicity of individual CTL and HTL epitopes to be used as the read-out. The organization of this program should allow for the critical evaluation of this therapeutic vaccine strategy within four years.